Bacterial pneumoniae and invasive pneumococcal disease are strongly associated with HIV-1 infection. Drug abusers have a higher incidence of pneumococcal pneumoniae co-infected with HIV, which increases their mortality rate. The overall goal of this application is to determine the mechanism(s) underlying opioid abuse increased susceptibility to severe pneumococcal pneumoniae. Our recent studies revealed that morphine abuse in a mouse model markedly increases mortality and compromises the innate immune response and increase susceptibility to S. pneumoniae infection. However, the signal transducing receptors and the cellular and molecular mechanisms for these effects are poorly understood. Our preliminary data indicates that morphine significantly decreases NF-kappaB activation, which is a key step for an appropriate innate immune response. Furthermore in our preliminary data we also show that morphine's effect is attenuated in the mu- opioid receptor knock out (MORKO) mice, but completely abolished by naltrexone. Based on these observations, we hypothesize that morphine induced defects in innate immunity is mediated through the opioid receptor by altering signal transducing that lead to NF-kappaB activation. This hypothesis will be addressed through two independent but interrelated specific aims. In specific Aim 1 we will investigate the type of opioid receptor that mediates morphine's effect using an in vivo S. pneumoniae infection model. MORKO and wild type (WT) mice will be used to determine the receptor type in the presence of delta and kappa antagonist. In specific Aim 2, we will investigate the cellular and molecular mechanisms by which morphine modulates NF-kappaB signaling and thereby impairs innate immune response to Streptococcus pneumoniae. An in vitro alveolar macrophage and lung epithelial cells infection model will be used to investigate cell population involved in morphine modulation initiation of innate immune response to pnumococcal infection, and to determine the signaling pathways underlying morphine regulation of S. pneumoniae induced TLRs dependent NF-:B activity. The proposed study should lead to better understanding of how opioid abuse increases the host's susceptibility to pulmonary infection and may guide the development of new treatment regimens for substance-abusing associated pneumoniae. Project Narrative: Drug abusers experience a higher rate of pneumoccocal infection, as well as, a higher mortality rate when co-infected with HIV. The proposed studies represent a unique series of experiments directed towards better understanding the underlying processes of an immune response, as well as, the role opioid abuse plays in suppressing such a response. Ultimately, the studies will afford better development and design options when treating substance-abusing associated pneumoniae. [unreadable] [unreadable] [unreadable]